由APC损失引起的结肠腺瘤发病和进展的两步模型
Reid A Phelps1, Stephanie Chidester, Somaye Dehghanizadeh
1Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
Cell
|May 20, 2009
概括
大肠腺多发性肠杆菌 (APC) 基因的丢失导致肠道细胞分化失败,但不会立即导致瘤生长. C端结合蛋白-1 (CtBP1) 驱动初始腺瘤的形成,而KRAS激活促进癌症的进展.
科学领域:
- 分子生物学分子生物学
- 癌症研究 癌症研究
- 发展生物学 发展生物学
背景情况:
- 异常的Wnt/β-catenin信号传递由于大肠腺瘤多重症 (APC) 损失是结肠腺瘤发病的一个关键事件.
- 关联APC损失与早期肠道瘤发生的精确分子机制尚不完全理解.
研究的目的:
- 调查APC损失在肠道细胞分化和增殖中的作用.
- 阐明在结肠腺瘤形成和进展中的APC损失下游的分子途径.
主要方法:
- 利用斑马鱼和人类细胞模型研究同卵性APC损失的影响.
- 分析了β-catenin的局部化,细胞分化标志物和增殖率.
- 评估了C端结合蛋白-1 (CtBP1) 和KRAS激活的参与.
主要成果:
- 同胞性APC损失导致肠道细胞分化失败,没有增加增殖或核β-catenin.
- 由APC突变引起的分化缺陷取决于CtBP1.
- 增加的扩散和核β-catenin积累需要额外的KRAS激活.
- 人类家族腺瘤多重症 (FAP) 腺瘤显示CtBP1上调没有核β-catenin,而癌症呈现核β-catenin.
结论:
- 单独的APC损失不足以启动β-catenin的核定位和扩散.
- 在APC损失后,CtBP1在腺瘤形成的初始阶段发挥着关键作用.
- KRAS激活和随后的β-catenin核定位对于腺瘤向癌症的进展至关重要.
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